Chest
Original Research: Pulmonary Vascular Disease: FeaturedEIF2AK4 Mutations in Pulmonary Capillary Hemangiomatosis
Section snippets
Study Participants
All participants provided written informed consent for genetic studies according to protocols approved by the institutional review boards (IRBs) of the participating institutions (Columbia University IRB #AAAA8979 and #AAAC0884; Intermountain Healthcare Urban Central Region IRB #1007044; Vanderbilt University IRB #9401).
We diagnosed PCH in two male siblings in a family (Fig 1). In 2004, PCH was diagnosed in the first sibling (II.1) at 20 years of age at the time of lung transplantation.
Exome Sequencing
Through our filtering process, we identified a gene (EIF2AK4) containing two novel, clearly pathogenic mutations: c.1153dupG (p.Val385fs) and c.3766C>T (p.Arg1256X) shared by both affected brothers (Fig 1). Both variants were confirmed in each brother by Sanger sequencing. Both unaffected parents were heterozygous carriers of one of the two mutations in EIF2AK4. The mother carried the frameshift mutation, c.1153dupG, and the father carried the nonsense mutation, c.3766C>T. The unaffected sister
Discussion
We report the identification of a novel gene, EIF2AK4, as a likely cause of autosomal-recessive PCH characterized by proliferation of small pulmonary capillaries. Whole-exome sequencing allowed us to identify two loss-of-function mutations in EIF2AK4 by analyzing only two affected brothers with PCH. We confirmed the role of EIF2AK4 in PCH by identifying two of 10 additional patients with no family history of PCH, each with two clear loss-of-function mutations. Previous reports suggested an
Conclusions
In conclusion, we identified mutations in EIF2AK4 as a novel genetic cause of PCH for some familial and sporadic patients with PCH. This finding provides a new opportunity to advance our understanding of the pathogenesis of PCH and pulmonary vascular biology.
Acknowledgments
Author contributions: Drs Best, Brown, and Elliott had full access to all data in the study and take responsibility for the data and the accuracy of the data analysis.
Dr Best: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.
Ms Sumner: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article;
References (21)
- et al.
Pulmonary capillary hemangiomatosis: a clinicopathologic review
Ann Thorac Surg
(1994) - et al.
Platelet-derived growth factor is increased in pulmonary capillary hemangiomatosis
Chest
(2007) - et al.
Pulmonary capillary hemangiomatosis with atypical endotheliomatosis: successful antiangiogenic therapy with doxycycline
Chest
(2003) - et al.
Pulmonary capillary hemangiomatosis: an immunohistochemical analysis of vascular remodeling in a fatal case
Chest
(2005) - et al.
Updated clinical classification of pulmonary hypertension
J Am Coll Cardiol
(2009) - et al.
Capillary haemangiomatosis of the lungs
Histopathology
(1978) - et al.
Pulmonary capillary haemangiomatosis in children and adolescents: report of a new case and a review of the literature
Eur J Pediatr
(2004) - et al.
Pulmonary capillary hemangiomatosis imaging findings and literature update
J Comput Assist Tomogr
(2007) - et al.
Pulmonary capillary hemangiomatosis. A report of three cases and a review of the literature
Am Rev Respir Dis
(1989) - et al.
Pulmonary capillary hemangiomatosis: a consideration in unexplained pulmonary hypertension
Chest
(2005)
Cited by (0)
Funding/Support: This research was supported in part by the National Institutes of Health [K23 HL098743; R01 HL060056; NIH 1P01HL108800-0] and Intermountain Research and Medical Foundation [1007044].
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.